EP0058959A1 - Method for preparing low-turbidity standard or reference sera - Google Patents

Method for preparing low-turbidity standard or reference sera Download PDF

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Publication number
EP0058959A1
EP0058959A1 EP82101284A EP82101284A EP0058959A1 EP 0058959 A1 EP0058959 A1 EP 0058959A1 EP 82101284 A EP82101284 A EP 82101284A EP 82101284 A EP82101284 A EP 82101284A EP 0058959 A1 EP0058959 A1 EP 0058959A1
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Prior art keywords
group
hydroxymethyl
serum
hydroxyl
hydrogen atom
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German (de)
French (fr)
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EP0058959B1 (en
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Helmut Dr. Rehner
Peter Dr. Roeschlau
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2496/00—Reference solutions for assays of biological material
    • G01N2496/05—Reference solutions for assays of biological material containing blood cells or plasma
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/106664—Blood serum or blood plasma standard or control
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/107497—Preparation composition [e.g., lysing or precipitation, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/108331—Preservative, buffer, anticoagulant or diluent

Definitions

  • the invention relates to a control or calibration serum with reduced tendency to form turbidity when reconstituted after previous lyophilization and a method for its production.
  • Control or calibration sera are natural sera of human or animal origin and serum-like artificial compositions with a precisely adjusted content of various serum components of interest, which are intended for calibration or for the control of methods for determining serum components.
  • Control or calibration sera which contain sensitive substances such as enzymes, bilirubin, lipoproteins, hormones etc., must be frozen for shelf life or after lyophilization at refrigerator temperature.
  • the process of lyophilization reduces the solubility of some components and consequently creates a turbidity in the reconstituted sample, which occurs especially when the control or calibration serum has higher lipid concentrations.
  • the turbidity of the control or calibration sera causes particular problems, especially when determining enzyme activities which are based on the NADH / NAD + measurement and, for. B. at 34o nm.
  • the turbidity of the sample can increase the already high absorbance of NADH in the reaction mixture so much that the resulting absorbance measurements have to be carried out in an extinction area of the photometer that is no longer precise. This means that the measurements become less accurate (i.e. the coefficient of variation (CV) of the determinations increases). Furthermore, the results obtained strongly depend on the quality of the photometer used.
  • This method has the advantage that a product of relatively low turbidity can be obtained without manipulating the control / calibration serum raw material.
  • a disadvantage is that this technology requires large investments and that the problem of lyogranulate filling has not yet been satisfactorily resolved, i. H. is not technically feasible on a larger scale.
  • a major disadvantage of this method is the fact that the precipitation of the ⁇ -lipoproteins by means of Ca 2+ / dextran sulfate and their separation results in a considerable increase in the price of the serum raw material.
  • Triton X 114 The addition of detergents (Triton X 114) is also critical. Test disturbances and / or enzyme inactivations are to be expected as a result.
  • This process has the advantage over processes 1) and 2) that conventional technology can be used and raw material reworking is avoided.
  • the turbidity of control / calibration sera produced by conventional methods from normal human serum is between 0.8 and 1.3.
  • Control / calibration sera which are produced by method 2), have a turbidity of approximately 0.3. However, the triglyceride or cholesterol content is very low after the ⁇ -lipoproteins have been separated off.
  • the invention is therefore based on the object of creating a calibration serum or control serum which shows a reduced tendency to form turbidity but does not have the disadvantages of the known solutions to this problem.
  • a control or calibration serum is characterized by a content of at least one compound of the general formula in which T is a hydrogen atom, a methyl, a hydroxymethyl or methoxymethyl group, X is a hydrogen atom, a hydroxymethyl group or methyl group if Y represents an OH group, a hydroxymethyl or NR 2 group, Y represents a hydrogen atom, a hydroxyl, hydroxymethyl or NR 2 group and Z represents a hydroxyl or O-CH 2 -CH 2 0H Group if Y is H or hydroxymethyl, or hydroxymethyl or carboxyl derivative, or
  • T is an ethyl or isopropyl group
  • X is hydrogen, methyl, methoxy or hydroxymethyl
  • Y is hydroxyl, hydroxymethyl or NR 2
  • Z is a carboxyl derivative and each R is independently a hydrogen atom or an alkyl group which may have a hydroxyl group and has 1 or 2 carbon atoms can, or / and the general formula II in which n represents a number from 2 to 8, in an amount sufficient to completely or partially prevent clouding in the reconstituted serum after prior lyophilization.
  • Carboxyl derivative here means carboxamides and esters and the carboxyl group itself.
  • the alkali or alkaline earth salts of the carboxylic acids can be used. If the concentration of the electrolytes is essential for the product, amines are advantageously used as the base.
  • P refer tertiary or quaternary amines, such as.
  • B the carboxylic acid salts of triethanolamine, tetramethylethylenediamine or tetramethylammonium.
  • the amount that a desired haze improvement will result largely depends on which compound is used.
  • the effective concentration for normal sera is usually between 0.5 to 10 g / dl.
  • the amount of feed required does not only depend on him, but is also determined by the matrix and its composition (e.g. by its lipid and protein content) and can therefore vary from case to case.
  • Examples of compounds which can be considered in the context of the invention are methanol, sodium acetate, triethanolammonium acetate, tetramethyldiethylene ammonium diacetate, sodium propionate, sodium lactate, alanine, sodium 2,2-bis (hydroxymethyl) propionate, N-methyldiethanolammonium -2,2-bis (hydroxymethyl) propionate, 2,2- (bishydroxymethyl) propionic acid amide, sodium 2-hydroxy-2-methylbutylate, valine, 2-methylamine, triethylene glycol, tetraethylene glycol and tetramethylammonium acetate.
  • the invention is particularly suitable for universal control or calibration sera, ie products which can be used for quality control or for calibrating (calibrating) machines for all clinically relevant serum parameters such as enzymes, substrates, metabolites, hormones, electrolytes etc. .
  • the invention is also suitable but also for control or calibration sera for special purposes, where z. B. can be dispensed with the addition of enzymes or hormones. Examples include lipid control serum or lipid calibration serum / lipid calibrator.
  • the serum as a whole more homogeneous, but also the precision of concentration and activity determinations of the parameters contained in the control / calibration sera is improved. This means that the target values for the individual parameters become safer and that the recovery of the declared target values is made easier for the user of the quality control sera or that the calibration of the devices is improved with these calibrators.
  • the extinction at this wavelength is mainly determined by the turbidity / inhomogeneity of the sample, the light absorption is relatively low.
  • the light intensity is therefore mainly weakened by light scattering effects.
  • the geometry of the measuring arrangement also influences the weakening of the light intensity caused by light scattering.
  • the extinctions are measured with a line spectrophotometer (Eppendorf 6115).
  • Reconstitution or reconstitution of the sample here means the addition of water or an aqueous solution (diluent) in the amount to the lyophilized sample that was present before lyophilization.
  • pooled human serum from healthy donors is used as the serum matrix.
  • the pooled serum was mixed with egg yolk extract in order to increase the concentration of the serum matrix of triglycerides to values of 16o to 27o mg / dl. The cholesterol content of the serum matrix was not changed.
  • the homogeneity of the reconstituted samples is improved by the additives.
  • the Ran e g (E max -E min) the turbidity of at least 11 individual sample bottle is much smaller, ie the product is uniform as a whole or homogeneous.

Abstract

Control serum containing (1) at least one compound of the formula: <IMAGE> (I) in which T is hydrogen or methyl, hydroxymethyl or methoxymethyl X is hydrogen hydroxymethyl or methyl when Y is hydroxyl, hydroxymethyl or NR2; Y is hydrogen, hydroxyl, hydroxylmethyl or NR2 and Z is hydroxyl or an -O-CH2-CH2OH group when Y is hydrogen or hydroxymethyl, or Z is hydroxymethyl or a carboxyl derivative or T is ethyl or isopropyl, X is hydrogen, or methyl, hydroxymethyl or methoxy, Y is hydroxy, hydroxymethyl or NR2 and Z is a carboxyl derivative; each R independently is hydrogen or an alkyl group with 1 to 2 carbon atoms optionally containing a hydroxy group and/or (2) at least one compound of the formula HO(CH2-CH2-O)nH, (II) in which n is an integer from 2 to 8, in an amount sufficient to reduce turbidities in reconstituted serum after previous lyophilization.

Description

Die Erfindung betrifft ein Kontroll- oder Eichserum mit verminderter Neigung zur Trübungsbildung bei Rekonstitution nach vorhergehender Lyophilisierung und ein Verfahren zu seiner Herstellung.The invention relates to a control or calibration serum with reduced tendency to form turbidity when reconstituted after previous lyophilization and a method for its production.

Als Kontroll- oder Eichseren werden natürliche Seren humaner oder tierischer Herkunft und serumähnliche künstliche Zusammensetzungen mit genau eingestelltem Gehalt an verschiedenen interessierenden Serumbestandteilen bezeichnet, die zum Eichen oder zur Kontrolle von Verfahren zur Bestimmung von Serumbestandteilen bestimmt sind.Control or calibration sera are natural sera of human or animal origin and serum-like artificial compositions with a precisely adjusted content of various serum components of interest, which are intended for calibration or for the control of methods for determining serum components.

Der Einsatz von Human- und tierischen Seren bzw. von Zusammensetzungen ähnlicher Art, die von Seren oder Plasmen abgeleitet sind, zur Herstellung von Kontroll- und Eichseren ist bekannt. Die Einstellung der Konzentration bzw. Aktivität klinisch relevanter Parameter (Substrate, Elektrolyte, Enzyme, Hormone) auf gewünschte Werte ist ebenfalls bekannt (Proc. Royal Soc. Med. 68 (1975) 624-629) .The use of human and animal sera or of compositions of a similar type, which are derived from sera or plasmas, for the production of control and calibration sera is known. The setting of the concentration or activity of clinically relevant parameters (substrates, electrolytes, enzymes, hormones) to desired values is also known (Proc. Royal Soc. Med. 68 (1975) 624-629).

Kontroll- bzw. Eichseren, die empfindliche Substanzen, wie Enzyme, Bilirubin, Lipoproteine, Hormone etc. enthalten, müssen aus Haltbarkeitsgründen tiefgefroren oder nach Lyophilisation bei Kühlschranktemperatur gelagert werden.Control or calibration sera, which contain sensitive substances such as enzymes, bilirubin, lipoproteins, hormones etc., must be frozen for shelf life or after lyophilization at refrigerator temperature.

Durch den Prozeß der Lyophilisation wird die Löslichkeit einiger Komponenten verringert und infolgedessen in der rekonstituierten Probe eine Trübung erzeugt, die vor allem dann auftritt, wenn das Kontroll- oder Eichserum höhere Lipidkonzentrationen aufweist.The process of lyophilization reduces the solubility of some components and consequently creates a turbidity in the reconstituted sample, which occurs especially when the control or calibration serum has higher lipid concentrations.

Dem Fachmann ist bekannt, daß Trübungen in Kontroll- bzw. Eichseren sehr unerwünscht sind. So können Probleme bei vielen spektrophotometrischen Methoden auftreten, wenn die Trübung der Probe nicht durch einen entsprechenden Probenleerwert berücksichtigt wird.The person skilled in the art is aware that clouding in control or calibration sera is very undesirable. Problems can occur with many spectrophotometric methods if the turbidity of the sample is not taken into account by a corresponding sample blank value.

Besondere Probleme verursacht die Trübung der Kontroll-oder Eichseren vor allem bei Bestimmungen von Enzymaktivitäten, die auf der NADH/NAD+-Messung beruhen und z. B. bei 34o nm durchgeführt werden.The turbidity of the control or calibration sera causes particular problems, especially when determining enzyme activities which are based on the NADH / NAD + measurement and, for. B. at 34o nm.

Bei Messungen bei 34o nm kann die Trübung der Probe (Kontroll- oder Eichserum) die ohnehin schon hohe Extinktion von NADH in der Reaktionsmischung zusätzlich so stark erhöhen, daß die resultierenden Extinktionsmessungen in einem nicht mehr präzisen Extinktionsbereich des Photometers durchgeführt werden müssen. Das bedeutet, daß die Messungen ungenauer werden (d. h. der Variationskoeffizient (VK) der Bestimmungen wird größer). Weiterhin hängen die erhaltenen Ergebnisse stark von der Qualität des verwendeten Photometers ab.For measurements at 34o nm, the turbidity of the sample (control or calibration serum) can increase the already high absorbance of NADH in the reaction mixture so much that the resulting absorbance measurements have to be carried out in an extinction area of the photometer that is no longer precise. This means that the measurements become less accurate (i.e. the coefficient of variation (CV) of the determinations increases). Furthermore, the results obtained strongly depend on the quality of the photometer used.

Man hat bereits versucht, das Trübungsproblem auf mehrere Arten zu lösen.Attempts have already been made to reduce the clouding problem to meh to solve other types.

1) Durch Schock-Freezing der Kontroll- bzw. Eichseren in Granulatform in einem geeigneten Gefrierbad, Lyophilisation der gefrorenen Granulate in Bulkform und Trockenabfüllung des erhaltenen Lyogranulats durch Wägung in geeigneten Flaschen (DE-OS 22 43 o14).1) By shock-freezing the control or calibration sera in granulate form in a suitable freezer bath, lyophilization of the frozen granules in bulk form and dry filling of the lyogranulate obtained by weighing in suitable bottles (DE-OS 22 43 o14).

Dieses Verfahren hat den Vorteil, daß ohne Manipulation des Kontroll-/Eichserum-Rohstoffs ein Produkt relativ niedriger Trübung zu erhalten ist. Ein Nachteil besteht darin, daß diese Technologie große Investitionen verlangt und daß das Problem der Lyogranulatabfüllung zur Zeit noch nicht befriedigend gelöst ist, d. h. technisch in größerem Umfang noch nicht durchführbar ist.This method has the advantage that a product of relatively low turbidity can be obtained without manipulating the control / calibration serum raw material. A disadvantage is that this technology requires large investments and that the problem of lyogranulate filling has not yet been satisfactorily resolved, i. H. is not technically feasible on a larger scale.

2) Durch Abtrennung der die Trübung hauptsächlich verursachenden ß-Lipoproteine aus den Seren und gegebenenfalls nachträglicher Aufstockung von Cholesterin mit einer geeigneten Lipoproteinfraktion (α-Lipoprotein) oder von Triglycerid mit Trioctanoin in Gegenwart von Triton X 114 (Clin. Chem. 22 (1976) 456-46o, 1299-13o5).2) By separating the ß-lipoproteins mainly causing the turbidity from the sera and, if necessary, subsequently adding cholesterol with a suitable lipoprotein fraction (α-lipoprotein) or triglyceride with trioctanoin in the presence of Triton X 114 (Clin. Chem. 22 (1976) 456-46o, 1299-13o5).

Ein wesentlicher Nachteil dieses Verfahrens ist darin zu sehen, daß das Ausfällen der ß-Lipoproteine mittels Ca2+/Dextransulfat und ihre Abtrennung eine erhebliche Verteuerung des Serumrohstoffs zur Folge hat.A major disadvantage of this method is the fact that the precipitation of the β-lipoproteins by means of Ca 2+ / dextran sulfate and their separation results in a considerable increase in the price of the serum raw material.

Ein anschließendes Aufstocken der Matrix mit einer geeigneten Lipoproteinfraktion zur Erhöhung der Cholesterin-Konzentration ist zwar möglich und bedingt eine mäßige Trübungszunahme (bei 3oo mg Cholesterin/ dl E ≳o,7), aber eine gleichzeitige Erhöhung der Triglyceridkonzentration ist damit nicht möglich.Subsequent replenishment of the matrix with a suitable lipoprotein fraction to increase the cholesterol concentration is possible and requires a moderate increase in turbidity (at 3oo mg cholesterol / dl E ≳o, 7), but a simultaneous increase in Triglyceride concentration is therefore not possible.

Kritisch ist ebenfalls der Zusatz von Detergens (Triton X 114). Teststörungen und/oder Enzyminaktivierungen sind hierdurch zu erwarten.The addition of detergents (Triton X 114) is also critical. Test disturbances and / or enzyme inactivations are to be expected as a result.

3) Durch Zusatz von Zuckern, Zuckeralkoholen und Aminozuckern zu den Kontroll- bzw. Eichseren, die die Denaturierung der Lipoproteine während der Lyophilisation verringern oder vermeiden (DE-OS 28 25 391).3) By adding sugars, sugar alcohols and amino sugars to the control or calibration sera, which reduce or avoid the denaturation of the lipoproteins during lyophilization (DE-OS 28 25 391).

Dieses Verfahren hat gegenüber den Verfahren 1) und 2) den Vorteil, daß die herkömmliche Technologie verwendet werden kann und eine Umarbeitung des Rohstoffs umgangen wird.This process has the advantage over processes 1) and 2) that conventional technology can be used and raw material reworking is avoided.

Nachteile dieses Verfahrens liegen darin, daß zum Teil große Mengen an "Stabilisator" zugesetzt werden müssen, wodurch sich die Eigenschaften des rekonstituierten Kontroll/Eichserums ändern (z. B. Viskosität) und daß es sich bei den Stabilisatoren um "physiologische" Stoffe handelt, die bestimmte Tests stören können (z. B. Störung der Glucosebestimmung nach der HK/ G6P-DH-Methode durch Glucose, Glucosamin, Fructose) .oder die sich möglicherweise im Serum verändern können (z. B. Hydrolyse von Saccharose oder Lactose durch α-Glucosidase, Invertase oder ß-Galactosidase, da diese Enzyme bei der Enzymaufstockung als sogenannte Enzymverunreinigungen in das Kontroll/Eichserum gelangen können).Disadvantages of this method are that sometimes large amounts of "stabilizer" have to be added, which changes the properties of the reconstituted control / calibration serum (e.g. viscosity) and that the stabilizers are "physiological" substances. which can interfere with certain tests (e.g. disturbance in glucose determination according to the HK / G6P-DH method by glucose, glucosamine, fructose) or which may change in the serum (e.g. hydrolysis of sucrose or lactose by α -Glucosidase, invertase or ß-galactosidase, since these enzymes can get into the control / calibration serum as so-called enzyme impurities when the enzyme is added).

Die Trübung (= Extinktion der unverdünnten, mit Wasser oder Diluent rekonstituierten Probe bei Hg 546 nm gegen Wasser gemessen) einer nach dem Verfahren 1) (Schock-freezing) hergestellten Prcbe beträgt etwa o,5.The turbidity (= absorbance of the undiluted sample reconstituted with water or diluent at Hg 546 nm against water) of a sample produced by method 1) (shock-freezing) is approximately 0.5.

Die Trübung von nach konventionellem Verfahren aus normalem Humanserum hergestellten Kontroll-/Eichseren (Lyophilisation der bei -3o°C bis -5o°C eingefrorenen Probe) liegt bei o,8 bis 1,3.The turbidity of control / calibration sera produced by conventional methods from normal human serum (lyophilization of the sample frozen at -3o ° C to -5o ° C) is between 0.8 and 1.3.

Kontroll-/Eichseren, die nach dem Verfahren 2) hergestellt sind, haben eine Trübung von etwa o,3. Der Gehalt an Triglycerid bzw. Cholesterin ist jedoch nach Abtrennung der ß-Lipoproteine sehr niedrig.Control / calibration sera, which are produced by method 2), have a turbidity of approximately 0.3. However, the triglyceride or cholesterol content is very low after the β-lipoproteins have been separated off.

Der Erfindung liegt daher die Aufgabe zugrunde, ein Eichserum bzw. Kontrollserum zu schaffen, welches eine verringerte Neigung zur Trübungsbildung zeigt, jedoch die Nachteile der bekannten Lösungen für dieses Problem nicht besitzt.The invention is therefore based on the object of creating a calibration serum or control serum which shows a reduced tendency to form turbidity but does not have the disadvantages of the known solutions to this problem.

Es wurde nun gefunden, und hierauf beruht die Erfindung, daß sich trübungsärmere und homogenere Kontroll-/Eichseren mit der herkömmlichen Technologie herstellen lassen, wenn man zu den Ansätzen auf Human- oder Tierserumbasis oder einer sonstigen von Serum oder Plasma abgeleiteten Zusammensetzung vor der Lyophilisation bestimmte organische, nicht zu den Zuckern gehörende Verbindungen zugibt.It has now been found, and the invention is based on this, that less turbid and more homogeneous control / calibration sera can be produced with conventional technology if one determines the approaches based on human or animal serum or another composition derived from serum or plasma before lyophilization organic compounds not belonging to the sugars.

Erfindungsgemäß ist ein Kontroll- oder Eichserum gekennzeichnet durch einen Gehalt an wenigstens einer Verbindung der allgemeinen Formel

Figure imgb0001
in der T ein Wasserstoffatom, eine Methyl-, eine Hydroxymethyl- oder Methoxymethylgruppe, X ein Wasserstoffatom, eine Hydroxymethylgruppe oder Methylgruppe, falls Y eine OH-Gruppe, eine Hydroxymethyl- oder NR2-Gruppe darstellt, Y ein Wasserstoffatom, eine Hydroxyl-, Hydroxymethyl- oder NR2-Gruppe und Z eine Hydroxyl- oder O-CH2-CH20H-Gruppe, falls Y gleich H oder Hydroxymethyl ist, oder Hydroxymethyl oder Carboxyl-Derivat bedeutet, oderAccording to the invention, a control or calibration serum is characterized by a content of at least one compound of the general formula
Figure imgb0001
 in which T is a hydrogen atom, a methyl, a hydroxymethyl or methoxymethyl group, X is a hydrogen atom, a hydroxymethyl group or methyl group if Y represents an OH group, a hydroxymethyl or NR 2 group, Y represents a hydrogen atom, a hydroxyl, hydroxymethyl or NR 2 group and Z represents a hydroxyl or O-CH 2 -CH 2 0H Group if Y is H or hydroxymethyl, or hydroxymethyl or carboxyl derivative, or

T eine Äthyl- oder Isopropylgruppe, X Wasserstoff, Methyl, Methoxy oder Hydroxymethyl, Y Hydroxyl, Hydroxymethyl oder NR2 und Z ein Carboxyl-Derivat bedeuten und jedes R unabhängig voneinander ein Wasserstoffatom oder eine gegebenenfalls eine Hydroxylgruppe tragende Alkylgruppe mit 1 oder 2 Kohlenstoffatomen sein kann, oder/und der allgemeinen Formel II

Figure imgb0002
in der n eine Zahl von 2 bis 8 darstellt, in einer Menge, die ausreicht, um Trübungen im rekonstituierten Serum nach vorheriger Lyophilisierung ganz oder teilweise zu verhindern.T is an ethyl or isopropyl group, X is hydrogen, methyl, methoxy or hydroxymethyl, Y is hydroxyl, hydroxymethyl or NR 2 and Z is a carboxyl derivative and each R is independently a hydrogen atom or an alkyl group which may have a hydroxyl group and has 1 or 2 carbon atoms can, or / and the general formula II
Figure imgb0002
 in which n represents a number from 2 to 8, in an amount sufficient to completely or partially prevent clouding in the reconstituted serum after prior lyophilization.

Unter "Carboxyl-Derivat" werden hier Carbonsäureamide und -ester sowie die Carboxylgruppe selbst verstanden.“Carboxyl derivative” here means carboxamides and esters and the carboxyl group itself.

Einen besonders starken Aufhellungseffekt weisen diejenigen Verbindungen der allgemeinen Formel I auf, welche Carboxylatgruppen aufweisen. Die zugrundeliegenden Carbonsäuren werden vor der Verwendung in der Erfindung neutralisiert.Those compounds of the general formula I which have carboxylate groups have a particularly strong lightening effect. The underlying carboxylic acids are neutralized before use in the invention.

Wenn bei Kontroll-/Eichseren der Elektrolytgehalt nicht von Bedeutung ist, können die Alkali- oder Erdalkalisalze der Carbonsäuren verwendet werden. Ist die Konzentration der Elektrolyte für das Produkt wesentlich, so verwendet man als Base vorteilhaft Amine. Bevorzugt werden tertiäre oder quartäre Amine, wie z. B. die Carbonsäuresalze von Triäthanolamin, Tetramethyläthylendiamin oder Tetramethylammonium.If the electrolyte content is not important for control / calibration sera, the alkali or alkaline earth salts of the carboxylic acids can be used. If the concentration of the electrolytes is essential for the product, amines are advantageously used as the base. Prefers tertiary or quaternary amines, such as. B. the carboxylic acid salts of triethanolamine, tetramethylethylenediamine or tetramethylammonium.

Die Menge, die eine gewünschte Trübungsverbesserung ergibt, hängt weitgehend davon ab, welche Verbindung verwendet wird. Die wirksame Konzentration für Normalseren liegt gewöhnlich zwischen o,5 bis 1o g/dl. Die benötigte Menge an Einsatzstoff hängt nicht nur von ihm selbst ab, sondern wird auch von der Matrix und ihrer Zusammensetzung bestimmt (z. B. durch deren Lipid- und Proteingehalt) und kann deshalb von Fall zu Fall variieren.The amount that a desired haze improvement will result largely depends on which compound is used. The effective concentration for normal sera is usually between 0.5 to 10 g / dl. The amount of feed required does not only depend on him, but is also determined by the matrix and its composition (e.g. by its lipid and protein content) and can therefore vary from case to case.

Es ist auch möglich, mehrere Substanzen der oben aufgeführten Art zusammen zum Serum bzw. zu der aus Serum abgeleiteten Matrix zuzusetzen. Sich gegenseitig verstärkende oder abschwächende Effekte können hierbei auftreten.It is also possible to add several substances of the type listed above together to the serum or to the matrix derived from serum. Mutually reinforcing or weakening effects can occur here.

Beispiele für Verbindungen, die im Rahmen der Erfindung in Betracht kommen, sind Methanol, Natriumacetat, Tri- äthanolammoniumacetat, Tetramethyldiäthylen-ammoniumdiacetat, Natriumpropionat, Natriumlactat, Alanin, Natrium-2,2-bis(hydroxymethyl)-propionat, N-Methyldiäthanolammo- nium-2,2-bis(hydroxymethyl)-propionat, 2,2-(Bishydroxyme- thyl)-propionsäureamid, Natrium-2-hydroxy-2-methylbuty- rat, Valin, 2-Metlvxyäthanol, Triäthylenglykol, Tetraäthylenglykol und Tetramethylammoniumacetat.Examples of compounds which can be considered in the context of the invention are methanol, sodium acetate, triethanolammonium acetate, tetramethyldiethylene ammonium diacetate, sodium propionate, sodium lactate, alanine, sodium 2,2-bis (hydroxymethyl) propionate, N-methyldiethanolammonium -2,2-bis (hydroxymethyl) propionate, 2,2- (bishydroxymethyl) propionic acid amide, sodium 2-hydroxy-2-methylbutylate, valine, 2-methylamine, triethylene glycol, tetraethylene glycol and tetramethylammonium acetate.

Die Erfindung eignet sich besonders für universelle Kontroll- bzw. Eichseren, d. h. Produkte, die zur Qualitätskontrolle bzw. zum Eichen (Kalibrieren) von Automaten für möglichst alle klinisch relevanten Serumparameter, wie Enzyme, Substrate, Metabolite, Hormone, Elektrolyte usw. verwendet werden können. Ebenso eignet sich die Erfindung aber auch für Kontroll- bzw. Eichseren für spezielle Zwecke, bei denen z. B. auf den Zusatz von Enzymen oder Hormonen verzichtet werden kann. Beispiele hierfür sind Lipidkontrollserum oder Lipideichserum/Lipidkalibrator.The invention is particularly suitable for universal control or calibration sera, ie products which can be used for quality control or for calibrating (calibrating) machines for all clinically relevant serum parameters such as enzymes, substrates, metabolites, hormones, electrolytes etc. . The invention is also suitable but also for control or calibration sera for special purposes, where z. B. can be dispensed with the addition of enzymes or hormones. Examples include lipid control serum or lipid calibration serum / lipid calibrator.

Erfindungsgemäß wird nicht nur das Serum als Ganzes homogener, sondern auch die Präzision von Konzentrations- und Aktivitätsbestimmungen der in den Kontroll-/Eichseren enthaltenen Parameter wird verbessert. Das bedeutet, daß die Sollwerte für die einzelnen Parameter sicherer werden und daß die Wiederfindung der deklarierten Sollwerte für den Benutzer der Qualitätskontrollseren erleichtert wird bzw. daß die Eichung der Geräte mit diesen Kalibratoren verbessert wird.According to the invention, not only is the serum as a whole more homogeneous, but also the precision of concentration and activity determinations of the parameters contained in the control / calibration sera is improved. This means that the target values for the individual parameters become safer and that the recovery of the declared target values is made easier for the user of the quality control sera or that the calibration of the devices is improved with these calibrators.

Die folgenden Beispiele erläutern die Erfindung weiter.The following examples further illustrate the invention.

Die Verringerung der Trübung wird wie folgt gemessen: Die Extinktion bei Ä = 546 nm der unverdünnten, mit Was- ser rekonstituierten Probe werden in einer 1 cm-Küvette gemessen und die Extinktionen von Proben mit Zusatz/Zusätzen mit Proben ohne Zusatz (= Kontrolle) verglichen.The reduction in turbidity is measured as follows: The absorbance at A = 546 nm of the undiluted, with W as-ser reconstituted sample in a 1 cm cell is measured and the absorbance values of samples with additive / additives with samples without addition (= control ) compared.

Die Extinktion bei dieser Wellenlänge wird vorwiegend von der Trübung/Inhomogenität der Probe bestimmt, die Lichtabsorption ist relativ gering. Die Lichtintensität wird also vorwiegend durch Lichtstreuungseffekte geschwächt. Die Geometrie der Meßanordnung (Lichtweg, Anordnung von Lichtquelle und -empfänger, Blende, Küvettenform etc.) beeinflußt die durch Lichtstreuung bedingte Lichtintensitätsschwächung ebenfalls.The extinction at this wavelength is mainly determined by the turbidity / inhomogeneity of the sample, the light absorption is relatively low. The light intensity is therefore mainly weakened by light scattering effects. The geometry of the measuring arrangement (light path, arrangement of light source and receiver, aperture, cuvette shape etc.) also influences the weakening of the light intensity caused by light scattering.

Die Extinktionen werden mit einem Linienspektralphotometer (Eppendorf 6115) gemessen.The extinctions are measured with a line spectrophotometer (Eppendorf 6115).

Rekonstitution bzw. Rekonstitutionierung der Probe bedeutet hier den Zusatz von Wasser oder einer wäßrigen Lösung (Diluent) in der Menge zur lyophilisierten Probe, die vor Lyophilisation vorlag.Reconstitution or reconstitution of the sample here means the addition of water or an aqueous solution (diluent) in the amount to the lyophilized sample that was present before lyophilization.

B e i s p i e 1 e 1 bis 15Example 1 1 to 15

Als Serummatrix wird in dieser Versuchsserie gepooltes Humanserum von gesunden Spendern verwendet. Um den trübungsaufhellenden Effekt der zugesetzten Substanzen besser zu demonstrieren, wurde das gepoolte Serum mit Eigelbextrakt versetzt, um die Konzentration der Serummatrix an Triglyceriden auf Werte von 16o bis 27o mg/dl zu erhöhen. Der Cholesteringehalt der Serummatrix wurde nicht verändert.In this test series, pooled human serum from healthy donors is used as the serum matrix. In order to better demonstrate the opacifying effect of the added substances, the pooled serum was mixed with egg yolk extract in order to increase the concentration of the serum matrix of triglycerides to values of 16o to 27o mg / dl. The cholesterol content of the serum matrix was not changed.

Nach Zugabe der Enzyme, Substrate, Elektrolyte oder Hormone zu der Serummatrix wurden die in Tabelle 1 aufgeführten Substanzen in der angegebenen Konzentration der Serummatrix zugesetzt. Danach wurden die Ansätze mit und ohne Zusatz keimfrei filtriert (o,2,u Membranfilterschicht), in Flaschen abgefüllt und lyophilisiert. Nach Rekonstitution mit Wasser wird die Trübung der Proben bestimmt.

Figure imgb0003
Figure imgb0004
Figure imgb0005
 After the enzymes, substrates, electrolytes or hormones had been added to the serum matrix, the substances listed in Table 1 were added to the serum matrix in the stated concentration. The batches were then filtered with and without the addition of aseptic (o, 2, u membrane filter layer), bottled and lyophilized. After reconstitution with water, the turbidity of the samples is determined.
Figure imgb0003
Figure imgb0004
Figure imgb0005

Die Ergebnisse der Tabelle 1 zeigen, daß meist 3 % zugesetzte Substanz ausreichen, um die Trübung des verwendeten Humanserums deutlich zu senken. Besonders effektiv sind Methanol, Acetat, Lactat und 2-Hydroxyisobutyrat.The results in Table 1 show that mostly 3% added substance is sufficient to significantly reduce the turbidity of the human serum used. Methanol, acetate, lactate and 2-hydroxyisobutyrate are particularly effective.

Weiterhin ist ersichtlich, daß die Homogenität der rekonstituierten Proben durch die Zusätze verbessert wird. Der Range (Emax -Emin) der Trübungen von mindestens 11 einzelnen Probenflaschen wird deutlich kleiner, d. h. das Produkt wird als Ganzes einheitlicher oder homogener.It can also be seen that the homogeneity of the reconstituted samples is improved by the additives. The Ran e g (E max -E min) the turbidity of at least 11 individual sample bottle is much smaller, ie the product is uniform as a whole or homogeneous.

B e i s p i e 1 e 16 bis 19B e i s p i e 1 e 16 to 19

Für diese Versuchsserie wurde gepooltes Human- oder Rinderserum verwendet. Der Lipidgehalt der Human- bzw. Tierserummatrix ist auf 35o bzw. 15o mg Cholesterin/dl und 3oo bzw. 15o mg Triglyceride/dl aufgestockt. Tabelle 2 faßt die Ergebnisse zusammen.

Figure imgb0006
Pooled human or bovine serum was used for this series of experiments. The lipid content of the human or animal serum matrix is increased to 35o or 15o mg cholesterol / dl and 3oo or 15o mg triglycerides / dl. Table 2 summarizes the results.
Figure imgb0006

Man erkennt, daß durch eine Verbindung der Formel I mit Z = COO zusammen mit einem geeigneten Kation die Trübung auch von lipämischen Seren stark verringert werden kann. Die Trübung von Beispiel 19 stimmt sogar mit der des nichtlyophilisierten Ausgangsmaterials überein.It can be seen that by means of a compound of formula I with Z = COO together with a suitable cation, the turbidity of lipemic sera can also be greatly reduced. The haze of Example 19 even matches that of the non-lyophilized starting material.

Claims (6)

1. Kontroll- oder Eichserum, gekennzeichnet durch einen Gehalt an wenigstens einer Verbindung der allgemeinen Formel I
Figure imgb0007
in der T ein Wasserstoffatom, eine Methyl-, eine Hydroxymethyl- oder Methoxymethylgruppe, X ein Wasserstoffatom, eine Hydroxymethylgruppe oder Methylgruppe, falls Y eine OH-Gruppe, eine Hydroxymethyl- oder NR2-Gruppe darstellt, Y ein Wasserstoffatom, eine Hydroxyl-, Hydroxymethyl- oder NR2-Gruppe und Z eine Hydroxyl- oder O-CH2-CH2OH-Gruppe, falls Y gleich H oder Hydroxymethyl ist, oder Hydroxymethyl oder Carboxyl-Derivat bedeutet, oder T eine Äthyl- oder Isopropylgruppe, X Wasserstoff, Methyl, Me thoxy oder Hydroxymethyl, Y Hydroxyl, Hydroxymethyl oder NR2 und Z ein Carboxyl-Derivat bedeuten und jedes R unabhängig voneinander ein Wasserstoffatom oder eine gegebenenfalls eine Hydroxylgruppe tragende Alkylgruppe mit 1 oder 2 Kohlenstoffatomen sein kann, oder/und der allgemeinen Formel II
Figure imgb0008
in der n eine Zahl von 2 bis 8 darstellt, in einer Menge, die ausreicht, um Trübungen im rekonstituierten Serum nach vorheriger Lyophilisierung ganz oder teilweise zu verhindern.1. control or calibration serum, characterized by a content of at least one compound of the general formula I.
Figure imgb0007
 in which T represents a hydrogen atom, a methyl, a hydroxymethyl or methoxymethyl group, X represents a hydrogen atom, a hydroxymethyl group or a methyl group if Y represents an OH group, a hydroxymethyl or NR 2 group, Y represents a hydrogen atom, a hydroxyl group, Hydroxymethyl or NR 2 group and Z is a hydroxyl or O-CH 2 -CH 2 OH group if Y is H or hydroxymethyl, or hydroxymethyl or carboxyl derivative, or T is an ethyl or isopropyl group, X is hydrogen , Methyl, methoxy or hydroxymethyl, Y hydroxyl, hydroxymethyl or NR 2 and Z represent a carboxyl derivative and each R independently of one another can be a hydrogen atom or an optionally hydroxyl-bearing alkyl group having 1 or 2 carbon atoms, and / or the general formula II
Figure imgb0008
 in which n represents a number from 2 to 8, in an amount sufficient to completely or partially prevent clouding in the reconstituted serum after prior lyophilization. 2. Serum nach Anspruch 1, dadurch gekenn-zeichnet, daß es o,5 bis 1o Gew.-% an Verbindung der allgemeinen Formel I oder/und II, bezogen auf rekonstituiertes Serum, enthält.2. Serum according to claim 1, characterized is characterized in that it contains 0.5 to 10% by weight of compound of the general formula I or / and II, based on the reconstituted serum. 3. Serum nach Anspruch 1 oder 2, dadurch gekennzeichnet , daß es wenigstens eine Verbindung der allgemeinen Formel I, in der Z eine Carboxylatgruppe darstellt, enthält.3. Serum according to claim 1 or 2, characterized in that it contains at least one compound of general formula I, in which Z represents a carboxylate group. 4. Verfahren zur Herstellung von trübungsarmen Eich-oder Kontrollseren durch Mischung der gewünschten Bestandteile in wäßriger Lösung, Lyophilisierung der Lösung und Rekonstitution des Lyophilisats mit wäßrigem Medium, dadurch gekennzeichnet , daß man vor der Lyophilisierung wenigstens eine Verbindung der allgemeinen Formel I
Figure imgb0009
in der T ein Wasserstoffatom, eine Methyl-, eine Hydroxymethyl- oder Methoxymethylgruppe, X ein Wasserstoffatom, eine Hydroxymethylgruppe oder Methylgruppe, falls Y eine OH-Gruppe, eine Hydroxymethyl- oder NR2-Gruppe darstellt, Y ein Wasserstoffatom, eine Hydroxyl-, Hydroxymethyl- oder NR2-Gruppe und Z eine Hydroxyl- oder O-CH2-CH20H-Gruppe, falls Y gleich H oder Hydroxymethyl ist, oder Hydroxymethyl oder Carboxyl-Derivat bedeutet, oder T eine Äthyl- oder Isopropylgruppe, X Wasserstoff, Methyl, Me-thoxy oder Hydroxymethyl, Y Hydroxyl, Hydroxymethyl oder NR2 und Z ein Carboxyl-Derivat bedeuten und jedes R unabhängig voneinander ein Wasserstoffatom oder eine gegebenenfalls eine Hydroxylgruppe tragende Alkylgruppe mit 1 oder 2 Kohlenstoffatomen sein kann, oder der allgemeinen Formel II
Figure imgb0010
in der n eine Zahl von 2 bis 8 darstellt, in einer das Auftreten von Trübung nach Rekonstitution verhindernden oder herabsetzenden Menge zusetzt.4. A process for the preparation of low-turbidity calibration or control sera by mixing the desired constituents in aqueous solution, lyophilizing the solution and reconstituting the lyophilizate with an aqueous medium, characterized in that at least one compound of the general formula I is used before the lyophilization
Figure imgb0009
 in which T represents a hydrogen atom, a methyl, a hydroxymethyl or methoxymethyl group, X represents a hydrogen atom, a hydroxymethyl group or a methyl group if Y represents an OH group, a hydroxymethyl or NR 2 group, Y represents a hydrogen atom, a hydroxyl group, Hydroxymethyl or NR 2 group and Z is a hydroxyl or O-CH 2 -CH 2 0H group if Y is H or hydroxymethyl, or hydroxymethyl or carboxyl derivative, or T is an ethyl or isopropyl group, X is hydrogen , Methyl, M e-thoxy or hydroxymethyl, Y hydroxyl, hydroxymethyl or NR 2 and Z represent a carboxyl derivative and each R independently of one another can be a hydrogen atom or an alkyl group which may have a hydroxyl group and has 1 or 2 carbon atoms, or the general formula II
Figure imgb0010
 in which n represents a number from 2 to 8, added in an amount to prevent or reduce the occurrence of turbidity after reconstitution. 5. Verfahren nach Anspruch 4, dadurch gekennzeichnet , daß man o,5 bis 1o Gew.-% an Verbindung der Formel I oder/und II zusetzt, bezogen auf rekonstituierte Lösung.5. The method according to claim 4, characterized in that o, 5 to 1o wt .-% of compound of formula I or / and II is added, based on the reconstituted solution. 6. Verfahren nach Anspruch 4 oder 5, dadurch gekennzeichnet , daß man eine Verbindung der Formel I verwendet, in der Z eine Carboxylatgruppe darstellt.6. The method according to claim 4 or 5, characterized in that one uses a compound of formula I in which Z represents a carboxylate group.
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